Thrombocytopenia In Liver Cirrhosis Research Articles

Management of Thrombocytopenia with Partial Splenic Embolization in Liver Cirrhosis

Thrombocytopenia is a frequent complication in patients with cirrhosis. Thrombocytopenia is generally divided into mild, moderate, and severe thrombocytopenia. Thrombocytopenia in liver cirrhosis not only increases the risk of bleeding during surgery but can also have an impact on patient management, such as liver biopsy, administration of antiviral therapy, and postponement of elective surgery. The pathophysiology of thrombocytopenia in chronic liver disease can be caused by decreased platelet production, sequestration in the spleen, and increased platelet destruction. Partial splenic embolization (PSE) is one option for treating thrombocytopenia in chronic liver disease. PSE is an effective procedure in treating complications associated with hypersplenism and portal hypertension, such as esophageal varices, pancytopenia, portal hypertensive gastropathy and ascites.

Hematological Abnormalities in Cirrhosis: A Narrative Review.

Liver cirrhosis remains a major public health issue. Liver fibrosis leading to cirrhosis is the terminal stage of various chronic liver diseases. Inflammatory cytokines are involved in the pathogenesis. Patients with cirrhosis often have hematological abnormalities, such as anemia and thrombocytopenia, which have multifactorial etiologies. Anemia in cirrhosis could be related to bleeding leading to iron deficiency anemia or other nutritional anemia such as vitamin B12 and folate deficiency. The pathophysiology of thrombocytopenia in liver cirrhosis has been postulated to range from splenic sequestration to bone marrow suppression from toxic agents, such as alcohol. It often complicates management due to the risk of bleeding with severely low platelets. This review aimed to highlightpathogenesis of liver cirrhosis, hematological abnormalities in liver cirrhosis, and their clinical significance.

B cell-activating factor is involved in thrombocytopenia in patients with liver cirrhosis

Liver cirrhosis (LC) involves B cells that produce anti-glycoprotein (GP) IIb/IIIa antibodies, found in primary immune thrombocytopenia (ITP). The role of autoimmunity in the pathology of thrombocytopenia in LC was investigated using 25 LC patients with thrombocytopenia, 18 ITP patients, and 30 healthy controls. Anti-GPIIb/IIIa antibody-producing B cells were quantified using enzyme-linked immunospot assay. Platelet-associated and plasma anti-GPIIb/IIIa antibody, plasma B cell-activating factor (BAFF), and a proliferation-inducing ligand (APRIL) levels were measured using enzyme-linked immunosorbent assay. B cell subset fractions and regulatory T cells (Tregs) were quantified using flow cytometry.The number of anti-GPIIb/IIIa antibody-producing B cells was significantly higher in LC patients than in ITP patients and healthy controls (both p < 0.001). Platelet-associated anti-GPIIb/IIIa antibodies were significantly higher in LC patients than in ITP patients and healthy controls (p = 0.002, p < 0.001, respectively). BAFF levels were significantly higher in LC patients than in ITP patients and healthy controls (p = 0.001 and p < 0.001, respectively), and APRIL levels were significantly higher in LC patients than in healthy controls (p < 0.001). Anti-GPIIb/IIIa antibody-producing B cells and platelet-associated anti-GPIIb/IIIa antibodies were positively correlated with BAFF levels in LC patients. LC patients had more naïve B cells and plasmablasts than healthy controls (p = 0.005, p = 0.03, respectively); plasmablasts were positively correlated with BAFF levels. LC patients had similar Tregs levels as ITP patients and healthy controls. Therefore, excessive BAFF production in LC patients with thrombocytopenia is likely associated with autoimmune B cell response, inducing anti-GPIIb/IIIa antibody production.

Outcomes of endoscopic intervention for overt GI bleeding in severe thrombocytopenia

Gastrointestinal bleeding (GIB) in the setting of thrombocytopenia raises concerns about endoscopic procedure risk. We aimed to assess the safety and outcomes of endoscopy for overt GIB in the setting of severe thrombocytopenia in liver cirrhosis (LC) and non-liver cirrhosis (NLC). This is a retrospective study on inpatients who underwent endoscopy within 24 hours of presentation for overt GIB with a platelet count (PC) of 20 to<50× 103/mL. Outcomes included diagnostic and therapeutic yields, procedural adverse events, packed red blood cell (pRBC) and platelet transfusions, recurrent bleeding rate, and all-cause and GIB-related mortality. One hundred forty-four patients were identified. The median PC was 41× 103/mL and 61% had LC. The diagnostic yield was 68% (LC= 61%, NLC= 79%, P= .04). Therapeutic yield was 60% (59% vs 60%, P= 1.00). The initial hemostasis rate was 94% with one adverse event. The median number of pRBC and platelet transfusions decreased after intervention in the entire cohort. Recurrent bleeding rates were 22% at 1 month and 30% at 1 year, with no differences between groups. An increased international normalized ratio (INR) >2 was a predictor of recurrent bleeding. All-cause mortality was 19% at 1 month and 37% at 1 year, whereas GIB-associated mortality in our cohort was only 3% at 1 month and 4% at 1 year, with no significant difference between LC and NLC. Predictors of mortality were INR >2, activated partial thromboplastin time >38 seconds, hypotension, intensive care unit admission, and pulmonary comorbidities. In this study cohort, we observed that endoscopy for overt GIB in the setting of severe thrombocytopenia in patients with LC and NLC appears safe, has moderate diagnostic and therapeutic yields with high initial hemostasis rate, and is associated with a significant decrease in pRBC and platelet transfusions. Recurrent bleeding and all-cause mortality rates remain high.

Partial splenic embolization for thrombocytopenia in liver cirrhosis: predictive factors for platelet increment and risk factors for major complications.

To investigate the predictors of platelet increment and risk factors for major complications after partial splenic embolization (PSE) in cirrhosis. Between March 2010 and June 2012, 52 cirrhotic patients with severe thrombocytopenia underwent PSE. Multiple variables were analyzed to identify the correlated factors affecting platelet increment and major complications after PSE. Linear mixed model analysis indicated the splenic infarction ratio (P < 0.001), non-infarcted splenic volume (P = 0.012), and cholinesterase level (P < 0.001) were significantly associated with the platelet increment after PSE. In receiver operating characteristic (ROC) analysis, the cut-off values of the splenic infarction ratio, and non-infarcted splenic volume for achieving an increment of ≥60.0 × 10(9)/L in platelet counts at 1 year after PSE were 64.3% and 245.8 mL, respectively. After PSE, eight patients developed major complications. Multivariate logistic regression analysis indicated major complications were significantly associated with the infarcted splenic volume (P = 0.024) and Child-Pugh score (P = 0.018). In ROC analysis, the cut-off values of these two factors for discriminating the uncomplicated and complicated were 513.1 mL and 9.5, respectively. The platelet increment after PSE depends on the splenic infarction ratio, non-infarcted splenic volume and cholinesterase level. But a large infarcted splenic volume and a high Child-Pugh score may cause complications. • The platelet increment after PSE greatly depends on the splenic infarction ratio. • The non-infarcted splenic volume significantly affects the efficacy of PSE. • A high cholinesterase level contributes to the improvement of thrombocytopenia after PSE. • The non-infarcted splenic volume significantly affects the relapse of hypersplenism. • Complications are significantly associated with the infarcted splenic volume and Child-Pugh score.

Management of thrombocytopenia due to liver cirrhosis: A review

Thrombocytopenia is a common complication in liver disease and can adversely affect the treatment of liver cirrhosis, limiting the ability to administer therapy and delaying planned surgical/diagnostic procedures because of an increased risk of bleeding. Multiple factors, including splenic sequestration, reduced activity of the hematopoietic growth factor thrombopoietin, bone marrow suppression by chronic hepatitis C virus infection and anti-cancer agents, and antiviral treatment with interferon-based therapy, can contribute to the development of thrombocytopenia in cirrhotic patients. Of these factors, the major mechanisms for thrombocytopenia in liver cirrhosis are (1) platelet sequestration in the spleen; and (2) decreased production of thrombopoietin in the liver. Several treatment options, including platelet transfusion, interventional partial splenic embolization, and surgical splenectomy, are now available for severe thrombocytopenia in cirrhotic patients. Although thrombopoietin agonists and targeted agents are alternative tools for noninvasively treating thrombocytopenia due to liver cirrhosis, their ability to improve thrombocytopenia in cirrhotic patients is under investigation in clinical trials. In this review, we propose a treatment approach to thrombocytopenia according to our novel concept of splenic volume, and we describe the current management of thrombocytopenia due to liver cirrhosis.

The role of thrombopoietin on the pathogenesis of thrombocytopenia in liver cirrhosis

The role of thrombopoietin on the pathogenesis of thrombocytopenia in liver cirrhosis

Restoration of thrombopoietin production after partial splenic embolization leads to resolution of thrombocytopenia in liver cirrhosis

The aim of this study was to evaluate the relation between thrombopoietin (TPO) and thrombocytopenia in patients with liver cirrhosis and those with idiopathic portal hypertension (IPH) before and after partial splenic embolization (PSE). We examined changes in platelet counts, liver function, megakaryocyte function, and plasma TPO levels after PSE in 30 patients (20 with liver cirrhosis, and 10 with IPH). Platelet counts in both cirrhosis and IPH increased significantly 2 months after PSE (cirrhosis group, 4.0±1.9 vs. 7.5±4.4×10 4/μl: P=0.0002; IPH group, 4.0±1.7 vs. 6.5±2.3×10 4/μl: P=0.0042). Plasma TPO level and prothrombin time increased significantly and alanine aminotransferase level (ALT) and total bilirubin level decreased significantly 2 months after PSE in the cirrhosis group (plasma TPO level, 0.57±0.30 vs. 0.72±0.27 fmol/ml: P=0.024), but not in the IPH group (0.56±0.21 vs. 0.55±0.34 fmol/ml: P=0.94). Moreover, the score of megakaryocytes with platelet production, an index of platelet production by megakaryocytes in bone marrow, increased significantly in the cirrhosis group. TPO production in cirrhotic patients is restored after PSE, leading to the resolution of thrombocytopenia. But patients with IPH had no change in liver function, indicating that only decreased spleen volume was responsible for the improvement in platelet count.

Plasma thrombopoietin levels in liver cirrhosis and kidney failure.

Recently, c-Mpl ligand (thrombopoietin, TPO) has been cloned by several groups and found to be a primary regulator of thrombopoiesis. Its mRNA expression has been detected in several organs including kidneys, bone marrow stroma cells, muscles, and is very strongly expressed in the liver. To clarify thrombopoiesis and the regulation of TPO in severe liver and renal failure. We analysed plasma TPO levels in patients with biopsy verified liver cirrhosis (n = 18; mean platelet count 115 +/- 54 x 109 L-1), in patients on chronic haemodialysis as a result of end-stage renal failure (n = 20; mean platelet count 295 +/- 94 x 109 L-1), and in healthy individuals (n = 20; mean platelet count 250 +/- 40 x 109 L-1). Plasma was prepared from EDTA-anticoagulated whole blood and a commercially available ELISA kit was used for the analysis. The mean plasma TPO concentration amongst the normal individuals was 50 +/- 14 pg mL-1. In the patients with liver cirrhosis and in patients on haemodialysis the mean TPO levels were 62 +/- 19 pg mL-1 and 46 +/- 17 pg mL-1, respectively. The mean plasma TPO concentration for the cirrhotic patients was significantly higher than the mean recorded for the healthy volunteers (P = 0.031), whereas no statistically significant differences in plasma TPO were seen between the group of end-stage renal failure and normals. Our results suggest that TPO production is maintained in liver cirrhosis and in renal failure, and that the thrombocytopenia in liver cirrhosis is not due to an impaired TPO production.

Thrombopoietic cytokines and reversal of thrombocytopenia after liver transplantation.

Thrombopoietin (TPO), the key regulator of platelet production, is mainly produced by the liver and reduced expression of TPO could cause thrombocytopenia in liver cirrhosis. Reversal of thrombocytopenia by orthotopic liver transplantation seems to be mediated through an increase in TPO plasma levels after transplantation, but other cytokines with thrombopoietic activity could augment the actions of TPO on post transplant platelet recovery. Measurement of thrombopoietic cytokines before and for 14 days post liver transplantation in a cohort of thrombocytopenic liver transplant patients. TPO, interleukin-3 (IL-3), IL-6, and IL-11 plasma levels as well as peripheral platelet count were analysed in thrombocytopenic patients with liver disease undergoing orthotopic liver transplantation (17 patients) and followed for 14 days after the intervention. Before liver transplantation, TPO plasma levels were undetectable and IL-3, IL-6, and IL-11 levels were normal. Sixteen out of 17 patients showed a significant rise of TPO levels within 2 days after transplantation, with a peak between days 4 and 6, while IL-3 and IL-6 levels did not show a significant rise. IL-11 levels remained normal. Platelet counts were significantly higher than pretransplantation levels by day 14 post transplantation. Restitution of normal TPO production by liver replacement seems to be of key importance for reversal of thrombocytopenia in liver disease. The early acting thrombopoietic factor IL-3 and the late acting factors IL-6 and IL-11 do not play a major role for recovery of peripheral platelet count after orthotopic liver transplantation.

Changes in Serum Thrombopoietin Levels after Splenectomy

To clarify the role of thrombopoietin (c-Mpl ligand, TPO) in ‘hypersplenic’ thrombocytopenia, we used an enzyme-linked immunosorbent assay to examine changes in serum TPO levels accompanied with splenectomy in 6 patients with liver cirrhosis, 4 patients with gastric cancer, and 2 patients with lymphoid malignancies. We also measured serum levels of other thrombopoietic cytokines such as interleukin-6 (IL-6) and erythropoietin. Platelet counts reached a maximum at day 14 after splenectomy in all subjects. In patients with liver cirrhosis, a lower elevation of platelet counts was observed compared with that in patients with gastric cancer. Serum TPO levels gradually elevated after splenectomy and reached a maximum 3.5 days after splenectomy in noncirrhotic patients, whereas peak serum TPO levels were delayed until day 7 in the cirrhosis group. IL-6 and erythropoietin showed similar kinetics between cirrhotic and noncirrhotic patients. These findings suggest that transient thrombocytosis after splenectomy may be associated with an alteration in the site of TPO catabolism by platelets from spleen to the blood and that deterioration of TPO production may play a role in thrombocytopenia in liver cirrhosis.

Reduced expression of thrombopoietin is involved in thrombocytopenia in human and rat liver cirrhosis.

It is widely accepted that thrombocytopenia associated with liver cirrhosis is caused by increased platelet destruction in the enlarged spleen, but this issue has not yet been analysed sufficiently in terms of platelet production. Thrombopoietin is produced mainly in the liver and strongly promotes platelet production. We studied serum thrombopoietin and the levels of its mRNA in liver tissue of cirrhotic patients and also in a rat model of liver cirrhosis. Furthermore, to clarify the influence of the spleen, we investigated thrombopoietin mRNA in splenectomized rats. The serum thrombopoietin level in humans with liver cirrhosis was not significantly reduced instead of thrombocytopenia. The expression of thrombopoietin mRNA in liver tissue decreased with the progression of liver cirrhosis in both patients and the rat model and no compensatory expression was observed in other organs or non-parenchymal cells. The level of thrombopoietin mRNA did not differ significantly in splenectomized cirrhotic rats before or after administration of dimethylnitrosamine, but was lower than that in splenectomized rats without cirrhosis. We conclude that thrombocytopenia in liver cirrhosis is caused not only by platelet destruction but also by decreased platelet production, perhaps due to reduction of thrombopoietin mRNA in the liver.

Evaluation of Thrombopoiesis in Thrombocytopenic Disorders by Simultaneous Measurement of Reticulated Platelets of Whole Blood and Serum Thrombopoietin Concentrations

To evaluate thrombopoiesis in thrombocytopenic disorders, we simultaneously determined reticulated platelet counts in whole blood by FACScan flow cytometry and serum thrombopoietin (TPO) concentrations by a sensitive sandwich ELISA. The subjects were 40 healthy volunteers and 45 thrombocytopenic patients. In idiopathic thrombocytopenic purpura (ITP), the percentage of reticulated platelets was significantly elevated (5.61 +/- 2.02%: mean +/- SD) relative to normal controls (2.17 +/- 0.90%), but serum TPO concentrations (1.91 +/- 1.27 fmol/l) did not differ significantly from the normal range (1.43 +/- 0.62 fmol/l). The patients with aplastic anemia (AA) had decreased reticulated platelet counts and markedly increased serum TPO concentrations (13.65 +/- 10.64 fmol/l). In thrombocytopenic patients with liver cirrhosis (LC), the absolute number of reticulated platelets (1.65 +/- 1.11 x 10(9)/l) decreased similarly that in AA. However, serum TPO concentrations (1.38 +/- 0.50 fmol/l) did not increase in contrast to AA. Our findings suggested a possible dual mechanism of thrombocytopenia in LC; that is, thrombocytopenia in LC results from the decreased TPO production primarily in the liver adding to an increase in platelet sequestration in the spleen.

Mechanism of thrombocytopenia in liver cirrhosis: kinetics of indium-111 tropolone labelled platelets.

Using indium-111 tropolone-labelled platelets, a study of platelet kinetics was performed on the basis of the relationship between platelet count, platelet survival time, platelet dynamics, platelet-associated immunoglobulin G (PA-IgG) and splenic volume in 31 patients with liver cirrhosis and a platelet count of less than 100 x 10(9)/l. The mean platelet count was 46.6 +/- 25.3 x 10(9)/l, and the mean platelet survival time was 6.50 +/- 1.33 days. The mean uptake into the spleen was 43.2% +/- 14.8% on the 1st day, and 53.7% +/- 14.3% on the 7th day. The mean PA-IgG level was 107.6 +/- 66.0 ng/10(7) platelets in five patients with chronic active hepatitis who were studied as controls, the mean platelet count was 197 +/- 30 x 10(9)/l, the mean platelet survival time 9.33 +/- 0.78 days, and the mean PA-IgG 21.2 +/- 2.9 ng/10(7) platelets. The former two parameters were significantly higher (P < 0.05), and the latter significantly lower (P < 0.05). In liver cirrhosis, the platelet count showed a positive correlation with the platelet survival time and a negative correlation with PA-IgG and the splenic volume. These results suggest that the increases in both the splenic platelet pool and platelet destruction in the spleen through immunological mechanisms may influence thrombocytopenia in liver cirrhosis.

Failure of two anti-platelet drugs (indobufen and dipyridamole) to improve thrombocytopenia in liver cirrhosis.

The hypothesis that thrombocytopenia in liver cirrhosis (LC) could be due to platelet activation was investigated. 18 patients with thrombocytopenia and LC have been studied. Circulating beta-thromboglobulin (beta TG) was normal, but appeared elevated when referred to platelet count. However, this may not accurately reflect alpha-granule release because of reduced liver cell function. Intraplatelet beta TG, on the contrary, should not be affected by liver cell function. It was markedly depressed, thus truly suggesting the existence of an exhausted state caused by platelet activation. Thromboxane B2 production was slightly increased. This could be due to a compensatory mechanism, or simply to platelet size, which was slightly increased, too. Anti-platelet therapy failed to improve thrombocytopenia. A platelet activation state seems therefore to be present in LC, but seems not to be the only cause of thrombocytopenia. Platelet factor 4 approximated zero, regardless of platelet count and therapy. This confirms that elevated values of such a protein represent only a laboratory artifact, due to platelet activation in vitro.